Only 15 % of pancreatic cancer patients'tumors are manageable via surgical resection. However, chemotherapy is often not effective because of drug resistance. Searching for a molecule (or protein) that affects drug resistance has become a focused theme in pancreatic cancer research. Preliminary studies Our preliminary studies show that;1) Nrf2 protein levels are frequently increased in both nucleus and cytoplasm in pancreatic cancer tissues and cell lines;2) significantly more active DNA-binding Nrf2(s) are present in cancer cells (comparing to normal cells);3) there are a good correlation between Nrf2 expression level vs. drug resistance;4) Nrf2 expression level affects the numbers of Hoechst 33342 positive cells;5) PI-103 affects Nrf2 transcriptional regulation activity;and 6) PI-103 reduces drug resistance in combination with chemotherapeutic drug. Hypothesis 1) Controlling Nrf2 expression level in pancreatic cancer will alter anti-tumor drug sensitivity. 2) Pretreatment of PI-103 will enhance cytotoxic effects of antitumor agents on pancreatic cancer. Aims We propose to;SA1) confirm if inhibition of Nrf2 activity reduces drug resistance in in vivo;SA2) identify the mechanism of PI-103 in sensitizing chemotherapeutic drug in pancreatic cancer cell lines;and SA3) test if PI-103 can sensitize chemotherapeutic drug in mice model. Significance Our study will provide a new treatment regimen for pancreatic cancer by suggesting Nrf2 as a target molecule and by testing a candidate small molecule that can increase drug sensitivity. PUBLIC HEALTH RELEVANCE: Pancreatic cancer is the fourth most common human malignant tumor;less than 5 percent of patients can survive longer than 5 years after diagnosis. Although anti-tumor drugs and radiation therapies are current treatment options for these cancers, drug resistance frequently occurs. Little is known about the molecular mechanisms in which pancreatic cancers are resistance to chemotherapeutic drugs. We recently found potentially important clues about this drug resistance. We found significantly elevated levels of a certain protein, called as a "Master protein", in human pancreatic cancer tissues and cell lines. This mater protein has been once considered as "a good guy" that is induced in response to oxidative stresses and protects normal cells by regulating its target gene products that neutralize the stress-associated harmful toxins (e.g., Reactive Oxygen Species). However, our findings implicate the elevated levels of the master protein can be "a bad guy" from the therapeutic viewpoint, for this protein can confer drug resistance to pancreatic cancer cells. Since the master protein's target gene products (proteins) are known to have the capacity to destroy or eliminate chemotherapeutic drugs, the increased amounts of these target proteins could confer drug resistance. In addition, our preliminary studies identified a small molecule which inhibits master protein's activity. When cells preincubated with the small molecule were challenged with anti-tumor agents (e.g., Cisplatin), we observed enhanced cell killing effects and decreased of the expression of the master and its target proteins in in vitro cell culture system. Therefore, we propose to further investigate the therapeutic value of this small molecule with combination of clinically relevant anti- tumor agent(s) (e.g., Gemcitabine) in in vivo animal model. Our long-term goal is to increase our ability to kill pancreatic cancer cells by controlling the amounts of these proteins and by developing new drugs based upon our initial findings.